The invention relates to a process of preparing pharmaceutical closures for containers made of flexible polymeric materials which arc suitable to be filled with parenterally administerable fluids prior to their sealing and sterilization. More particularly, closures are prepared which have an excellent resealing capacity after being penetrated by a piercing device for establishing fluid communication with the container, even after multiple entries into the container.
The efforts of providing containers of polymeric materials for parenterally administerable products which are sterilizable after being finally tilled and assembled, but also safe from migration of potentially hazardous agents and easy to recycle, have been previously disclosed in the International patent applications WO 95/08317, WO 97/37628 and WO 97/39952 which all are incorporated herein as references
EP 0 097 054 (Hantakki Oy) discloses a flexible bag for medical fluids provided with an injection port which has a closure comprising a shielded resilient pierceable pad which rescals after penetration and which also may be protected from the stored fluids. This type of closure has the drawback in that it is quite complicated to assemble from different parts in the moment of sealing the ports and therefore is less suitable in an aseptic environment.
U.S. Pat. No. 4,303,067 (American Hospital Supply Corp.) describes an additive port for a medical bag through which medicals can be supplied by an injection device. The port has a puncturable, reasealable plug made of an elastomer. Nothing is disclosed about the resealing capacity or the sterilizability of the closure.
U.S. Pat. Nos. 4,975,308 and 5,247,015 describe molded stoppers for blood tubes made of a halobutyl rubber dispersed in a mixture of polyolefins and a thermoplastic elastomer. No disclosures are given herein about their resealing capacity after needle penetration or their capacity of being heat sterilized.
There are numerous other citations in the literature of closures for pharmaceutical containers of various types, both made of glass or of polymeric materials which are disclosed to be suitable to seal stored fluids for parenteral administration. Generally, it is a requirement from medical authorities that such closures must be capable of maintaining a barrier against the environment, both during sterilization by steam and during subsequent long term storage. It is also required that this type of closures shall be capable to reseal spontaneously and immediately after the withdrawal of a penetrating needle. They must also have a resealing capacity after multiple entries by penetrating needle, a cannula or a similar penetrating device suitable for collecting fluid from the container or for adding a component to be mixed with the contents of the container. An improper resealing of the closure after penetration potentially will waste the integrity of stored fluids by providing a channel for microbial growth into the container. It is also a requirement that the container must not leak when its closure is penetrated during fluid connection, for instance during infusion to a patient through a cannula. Furthermore, the closure must be compatible with stored fluids and no migration of potentially hazardous agents from any of its parts is allowed. The closure must also withstand conventional sterilization processes including autoclavation at 121xc2x0 C. and sterilization by irradiation without losing any of its sealing capacity. It is also a requirement set by an increasing amount of medical authorities that each authorized container must be possible to recirculate and its therefore a demand that empty containers shall be possible to dispose without laborious disassembling and sorting of parts for individual recycling processes.
In the aforementioned International patent application WO 97/39952, ports for containers storing parenterally administerable fluids having closures generally fulfilling several of these requirements are disclosed which are designed to have all important parts correctly sterilized by pressurized steam in the autoclave. These closures typically comprise a frame or carrier part for a penetrable plug, wherein said carrier is adapted to seal an orifice by weak seal weldings or by being clamped in the orifice of the container. The penetrable plug of the closure is intended to be pierced by a device for establishing fluid communication with the container e.g. an injection syringe. As described in the previously mentioned Swedish patent application SE 9601540-9, such a closure can be produced in a two-color mold process wherein the generally sleeve formed carrier first is molded of thermoplastic material in a desired shape to sealingly fit with a container orifice, whereupon liquefied thermoplastic elastomer is injected into the sleeve to form the penetrable plug. These closures are highly advantageous over prior art sealing means by their simple production process and their comparatively simple assembly in a scaling position in a container orifice without extra time consuming steps, where their various parts must be assembled to form an adequate sealing device.
It is, however, a considerable technical problem to repeatedly manufacture this type of closures under conditions such that the elastomer plug obtains suitable characteristics of being resealable after multiple entries into the container by piercing devices, while it at also at the same time must form scaling adhesive bondings along the contact surface with the inner periphery of the carrier, so the two-part closure perfectly may seal against the environment. In particular, it has been connected with problems to find a reliable process which is reproducible in giving the penetrable plug specific resealing characteristics in a conventional two-part molding technique. This type of closure must also preferably be capable of forming a reliable seal with the container orifice, for example by forming weak seal weldings, as described in the above mentioned International patent application WO 95/08317.
It is an object of the present invention to provide a process for manufacturing pharmaceutical closures with a pierceable plug of an elastomeric material which safely reseals itself after being pierced with a syringe, a cannula or similar device capable of adding or withdrawing a fluid from a medical container.
It is also an object of the invention to provide a process which is highly reproducible in giving the pierceable plugs a resealing capacity after being pierced at least according to the DIN 58 363 part 15 standard.
It is a further object of invention to provide such a method of preparing pierceable plugs in a two-part injection molding technique to form adhesive bondings of an elastomer part and a carrier part in a highly reliable manner without employing any bonding agents and with low risk of contamination, while at the side time avoiding the formation of cavities between the two parts.
Another object of the present invention is the provision of pharmaceutical closures which consists of polyolefins to such an extent that both the closure and the polyolefinic container body can be recycled together without being disassembled and separately collected, while having a resealing capacity at least according to the DIN 58 363 part 15 standard.
A further object of the present invention is to provide pharmaceutical closures with the mentioned resealing capacity which are possible sterilize by high pressure steam (autoclavation) or by irradiation in a single process after being assembled with the container and maintain its integrity and other important characteristics, while being compatible with substantially all infusion fluids including lipophilic fluids like lipid emulsions without causing migration of potentially toxic agents.
A still further object of the present invention is to provide pharmaceutical closures of a two-part comprising a pierceable plug of an elastomer in a carrier part wherein said carrier part is provided with means for deleting cavities formed during the manufacturing process.
The present invention is directed to a method of preparing pharmaceutical closures of a two-part type comprising a generally sleeve-formed carrier made of a polyolefinic material coaxially enclosing a generally cylindrical elastomeric penetrable plug. The carrier part is separately formed in a molding process, whereupon heated elastomer is introduced into said carrier in an injection molding process with conventional injection molding tools, at a high pressure to form a penetrable plug. A characteristic feature of the method is that it allows for a relaxation period of the thermoplastic material in the injection molding tool to settle and develop its resealing characteristics. The relaxation is generated by letting the high pressure be lowered to a reduced overpressure level during a controlled relaxation period and by subsequently gradually reducing the overpressure to an atmospheric pressure over a prolonged cooling period. Another feature of the method is to, before the elastomer is introduced cooling the carrier from its high forming temperature to a temperature well above room temperature but not exceeding about 60xc2x0 C.
By such a method suitable adhesive bondings are provided in the contact surface between the carrier and the elastomer plug while the elastomer material is allowed to relax in a controlled manner. The relaxation period and subsequent cooling and settling period leads to a relaxation on a molecular level which surprisingly enhances the recovery characteristics of the elastomer material, so it obtains an excellent rescaling capacity.
The elastomer is heated to fluidity, or to reasonable flow characteristics, which typically means to a temperature exceeding 180xc2x0 C., dependent on the selected thermoplastic elastomer. By the specific features of the carrier part, more closely described below, air will be spontaneously evacuated from its inside when the heated elastomer is injected under high pressure which obstructs the formation of air cavities or bubbles in the elastomer and in the region between the elastomer and the carrier.
After the high pressure introduction in the carrier, the pressure is released to a lower level of overpressure and during this relaxation period more heated elastomer can be reintroduced into the carrier to compensate for any shrinking effect, when the elastomer is cooled. Preferably, to obtain the suitable resealing characteristics with said method, the relationship between the magnitude of the reduced over pressure and high pressure is about between 1:2 and 1:5, a preferred relationship is about 1:3.
The initial high pressure level in the injection molding is preferably at least about 20 bar, but not exceeding about 50 bar. The reduced overpressure exerted during the relaxation period is preferably not more than about 17 bar.
Preferably the high pressure step and the subsequent relaxation step has about the same duration. The high pressure step, has a preferred duration of about 3 to 5 seconds, and most preferably about 4 seconds, while the controlled relaxation period has a duration of more than one second, but does preferably not exceed five seconds, most preferably it has duration of about 3 three seconds. The subsequent cooling period preferably is preferably is longer than the sum of the high pressure step and the controlled relaxation step. Preferably the cooling step is about 10 to about 20 seconds.
The method according to the present invention can be performed by conventional injection molding equipment. The person skilled in this field of technology will have no difficulties in finding suitable equipment to mold the carrier part in a desired shape and to transfer it in the protected environment of a two-part molding station and fill it with an injected heated, flowing elastomer under high pressure.
The carrier is preferable essentially consisting of medical grade polyolefins which may be compounded with a fraction of thermoplastic elastomer and shall generally be capable of scaling the container orifice, for example by forming weak seal weldings with a compatible material of the container orifice. Preferably, the polyolefin is polypropylene or polyethylene based which means that it essentially consists of polypropylene or polyethylene, optionally with a fraction copolymerized ethylene or propylene. Various medical grades of pure polypropylene or polyethylene are also conceivable materials
The elastomer material for production of the resealable plug preferably comprises a polyolefin compatible with the carrier and a thermoplastic elastomer. Suitable commercially available materials are Dynaflex(copyright) from GLS Corp., containing polypropylene and SEBS (styrene-ethylene-butadiene-styrene), Santoprene(copyright) containing polypropylene and EPDM-rubber, Evoprene(copyright) from Evode, Cflex and Craiwton(copyright), as well as and various materials containing polyisobutylene (PIB).
The inventive method will specifically be useful for preparing pharmaceutical closures with a penetrable plug made of elastomer which has a resealing capacity which fulfills at least the requirements of standard norm DIN 58 363 Part 15 that it should be reasealable after a penetration with a 0.6 mm needle without any escape of fluid.